The function of heat shock protein genes (HSP) and their gene products (HSP) is a very complicated genetics/genomics issue, but directly relevant to ‘gene-enviroment interactions’ and ‘personalized medicine’. These two [attached] publications (combined), plus the editorial, describe even further the difficulty with ever imagining the day might come for RELIABLE genetic risk prediction of drug response (or response to any environmental toxicant) by looking at DNA sequence (genomic mutations) alone. As we at GEITP have often emphasized, besides genetic (DNA sequence) differences, there are epigenetic differences (DNA methylation, RNA-interference, histone modifications, chromatin remodeling) plus constant environmental effects (lifestyle, diet, exercise, smoking, other medicines, etc., even transgenerational) –– that all contribute to the phenotype (trait).

For example, hundreds of mutations can cause Fanconi Anemia (FA), a blood-cell deficiency that predisposes people to cancer, but the mutation in any given patient is a very poor predictor of whether they will have mild or severe disease. Understanding how context alters outcomes in this way lies at the heart of personalized medicine. The two attached publications [one in Cell, the other in Nat Struct Mol Biol) now provide compelling mechanisms by HSP90 alters outcomes associated with genetic differences. HSP90 is well known as a “molecular chaperone” that maintains the structural integrity of cell-signalling proteins. Experiments in fruit flies by a colleague and friend, the late Susan Lindquist, almost 20 years ago, showed that impairing HSP90 function causes diverse, strain-specific outcomes –– eye defects in one fly strain, wing defects in another, and so on.

Later studies in other animals, plants and fungi gave similar results, supporting the notion that HSP90 modulates the consequences of genetic variation in many species. But how, exactly, HSP90 does this –– has been subject to speculation and debate. Karras & coworkers [1st paper, attached] showed that human HSP90 alters effects of genetic mutations, by directly interacting with mutant proteins; they studied mutations in FANCA, the gene most commonly mutated in people with FA. Cells of these patients are typically hyper-sensitive to the DNA-damaging agent mitomycin C. Because FANCA protein is involved in repairing DNA damage, mitomycin C can be used to diagnose FA and to measure how severely a mutation disrupts cellular function.

Karras et al. found that some mutant FANCA proteins show greater physical association with HSP90 than others, and that, in general, these mutant proteins were associated with less-severe disruption of cellular function. Inhibiting HSP90 increased the susceptibility to mitomycin C in cells producing these mutant FANCA proteins, confirming a long-hypothesized mechanism of HSP90 action. According to this hypothesis, the chaperone stabilizes otherwise defective proteins –– allowing them to fold into a somewhat normal formation that enables them to partially function. Remarkably, the effect of HSP90 inhibition on sensitivity to mitomycin C could be mimicked by increased temperature, an environmental stressor that impairs HSP90 function and that might occur if a patient has a fever. Thus, the ability of FANCA to interact with HSP90 can influence the course of disease, which is dependent on both genetic and environmental context.

In the second attached paper, Hummel & coworkers discovered a role for HSP90 in modulating the effects of endogenous retroviruses (ERVs) –– DNA sequences derived from viruses that have inserted copies of themselves into host DNA. ERVs can increase in number, in a host genome, either by reinfection or by replicating in cells that form sperm or eggs; these ERVs comprise ~5–10% of human and mouse genomes. Presence or absence of some ERV insertions differs between people (and between mice). Transcription of ERVs can stimulate the activity of adjacent genes. Authors profiled gene-expression patterns in three mouse cell types, after HSP90 inhibition, which showed that HSP90 counteracts this activating tendency.

The researchers demonstrated that HSP90 interacts with the protein KAP1, which directs the deposition of repressive molecular modifications on ERV DNA to prevent transcription. HSP90 inhibition prevents KAP1-mediated repression of ERVs. Thus, the authors propose that HSP90 activity enables accumulation of different ERV insertions in different individuals. These insertion differences would be inconsequential –– under normal conditions –– but could lead to diverse outcomes in times of stress. If this holds true in humans, it would be predicted that clinical presentation of disease traits could be dramatically affected by ERV-insertion differences between individuals.

These two breakthrough studies add to a growing literature that establishes the abundance of ‘cryptic’ genetic variation –– which has no effect on phenotype under normal conditions, but lurks in populations until other mutations or environmental perturbations reveal it. The papers also point to implications for future research. First, HSP90 not only suppresses effects of certain genetic differences, but can also cause mutant proteins to adopt new functions, potentiating differences. Second, consider the potential effects on so-ca;;ed “personalized medicine.” If mechanisms that shield and release cryptic genetic variation are numerous and varied, then each individual might be a special case –– thereby limiting our power (EVER) to predict how sets of genetic and environmental conditions will influence disease outcomes or alter the effectiveness of drug response or treatments, etc. [ ! ! ! ! ]